JPH05504141A - therapeutic drugs - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] therapeutic drugs The present invention provides novel therapeutic agents, in particular: (1) penzovirano(4,3-c)pyrazole; Methods for their production, pharmaceutical compositions containing them and them as immunomodulatory drugs Regarding the therapeutic activity of.

The present invention provides the following formula I [Wherein, R is hydrogen, cyano, C2-1 alkanoyl, C2-. alkoxy group Ponil, CONH. or R1 is C1-6 alkyl or C2-6 alkyl. rukenyl, both of which are soano, halo, triflicyl, methyl, hydroxy , benzoyl, C2-6 alkanoyl, C2-1 cycloalkoxy, Nyl, a 5- to 7-membered non-aromatic heterocyclic group containing two oxygen heteroatoms, CONR ,R. Optionally substituted with phenoxy or C1-6 alkoxy, which Among them, C1-6 alkoxy is furthermore halo, hydroxy, C+-s alkoxy or may be substituted with C2-6 alkanoyloxy.

R2 represents hydrogen or chloro: R2 represents chloro or trifluoromethyl; or R2 and R3 are bonded; Forms a fused benzene ring: R4 is hydrogen, C1-6 alkyl, C1-, alkoxy Or represent a halo.

R1 and R1 may be the same or different and are hydrogen, Cl-6 alkyl or benzyl] or their pharmaceutically acceptable salts. Ru.

Groups containing a chain of three or more carbon atoms may be straight chain or branched. For example, propyl includes n-propyl and isopropyl, and butyl includes n-butyl. It was found to include 5ec-butyl, isobutyl and tert-butyl. There will be. The term "halo" includes fluoro, chloro or bromo.

Preferably R1 is hydrogen, cyano, carbamoyl, C2-4 alkanoyl (e.g. acetyl), C2-4 alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), or -C)IzR1o, where R1° is hydrogen. , cyano, trifluoromethyl, halo, hydroxy, C34 cycloalkoxyca Rubonyl (preferably cyclobutoxycarbonyl), benzoyl, C0NHRi (e.g. carbamoyl, methylcarbamoyl, ethylcarbamoyl or furocarbamoyl) vilcarbamoyl) or two oxygen heteroatoms (e.g. 1,3-dioxolane -2-yl or 1,3-dioxan-2-yl) or RIG represents a heterocyclic group: C1-, alkyl (e.g. methyl, ethyl or propyl, more preferably methyl or ethyl) or C2-4 alkenyl (e.g. vinyl), and in some cases hydroxy, cyano, tri- Fluoromethyl, halo (preferably chloro or bromo), CI-, alkoxy (preferably methoxy or ethoxy), C1-5 alkoxy (C,,)alco (preferably 2-methoxyethoxy), C2-alkanoyloxy (CI -g) alkoxy (preferably acetoxyethoxy), hydroxy (C, ~, a alkoxy) (preferably 2-hydroxyethoxy), C,, alkanoyloxy (preferably acetoxy or propionyloxy), phenoxy, benzoyl , CONHRI (e.g. carbamoyl, methylcarbamoyl, ethylcarbamoyl) or propylcarbamoyl) or two oxygen heteroatoms (e.g. 1,3 -dioxolan-2-yl or l,3-dioxan-2-yl) It is a group substituted with a ~7-membered non-aromatic heterocyclic group.

In preferred compounds, R5 represents (CH2), J, where J is hydrogen , C3-8 alkoxy, cyano, halo or carbamoyl, P is 0, l or 2, R1 is especially hydrogen, methyl, cyanomethyl, (CH,)2 halo, Represents carbamoylmethyl or C3-4 alkoxyethyl.

Preferred substituents R1 are: Hydrogen, methyl, ethyl, propyl, butyl, allyl, 2-methoxyethyl, 2- ethoxyethyl, 2-ethoxypropyl, 2-(2-methoxyethoxy)ethyl, 2-(2-acetoxyethoxy)ethyl , 2-(2-hydroxyethoxy)ethyl, cyclobutyroxycarbonylmethyl, Carbamoyl, methylcarbamoylmethyl, 2-carbamoylethyl, 3-cal Bamoylpropyl, ethylcarbamoylmethyl, propylcarbamoylmethyl, Isopropylcarbamoylmethyl, benzyl(methyl)carbamoylmethyl, carbonate Rubamoylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-acetyl Toxyethyl, cyano, cyanomethyl, 2-cyanoethyl, 2-phenoxyethyl 2-chloroethyl, 2-bromoethyl, 2,2.2-trifluoroethyl, 2-propionyloxyethyl, 1,3-dioxolan-2-ylmethyl, 2-(1,3-dioxan-2-yl)ethyl, 2-(1,3-dioxolane- 2-yl)ethyl, acetyl, benzoylmethyl, and ethoxycarbonyl.

In particularly preferred compounds R1 represents methyl or 2-ethoxyethyl.

In preferred compounds of formula I R2 represents hydrogen.

In preferred compounds of formula I, R1 is chloro or trifluoromethyl, more Preferably it represents trifluoromethyl.

In preferred compounds of formula I, R4 is hydrogen, C1_4alkyl, Cl_4alkyl Represents koxy, fluoro, chloro, or bromo. More preferably R4 is hydrogen , methyl, methoxy or ethoxy, most preferably hydrogen or methoxy. Was.

Preferably R1 is hydrogen, methyl or ethyl or benzyl, especially hydrogen or Represents methyl.

Preferably R9. represents hydrogen or benzyl.

Specific compounds of formula ■ are listed in the table provided in the specific examples of the invention. Compounds shown in the table or pharmaceutically acceptable salts thereof.

Compounds of formula I may contain one or more chiral centers and may contain a variety of chiral centers. Exists in optically active form.

When a compound of formula I contains one chiral center, the compound has two enantiomers. The present invention encompasses both enantiomers and mixtures of enantiomers. . Enantiomers can be determined by methods known to those skilled in the art, e.g. By forming salts or separable complexes of stereoisomers, and by crystallization: Formation of separable derivatives of norastereoisomers, e.g. crystallization, gas-liquid or By liquid chromatography: separation of one enantiomer by reaction with an enantiomer-specific reagent selective derivatization of sexual forms, e.g. by enzymatic oxidation or reduction: chiral environments, e.g. on a chiral support, e.g. silica with an attached chiral ligand or on a chiral solvent can be resolved by gas-liquid or liquid chromatography in the presence of . substitute A particular enantiomer should be treated with an optically active reagent, substrate, catalyst or solvent. The asymmetric synthesis used or the conversion of one enantiomer into the other by asymmetric rearrangement It can be synthesized by converting it into a sex form.

For example, the following compounds may also exist in R- or S-enantiomeric form: 4-(4-chlorophenyl)-2-(2-ethoxypropyl)[1]-benzopy Lano(4,3-c)pyrazol-3(2H)-one.

When a compound of formula I contains one or more chiral centers, the compound May exist in the form of isomers. The present invention relates to each diastereoisomer and diastereoisomer. Includes mixtures of isomers. Diastereoisomers are experts in their field of technology. separation by methods known to those skilled in the art, such as crystallization or liquid chromatography. Wear.

Certain compounds of formula ■ may exist in various tautomeric forms or in various geometric It can exist as a sexual body.

Certain compounds of formula ■ may exist in more than one crystalline form. and mixtures thereof.

Certain compounds of formula I may also exist in solvated forms, such as hydrates, or The invention encompasses each solvate and mixtures thereof.

The present invention also provides a therapeutically effective amount of a formula containing a pharmaceutically acceptable diluent or carrier. (2) includes pharmaceutical compositions containing the compound;

As used hereinafter, the term [active compound] refers to CI of formula I]benzopyranoC4,3- c) means pyrazole. In therapeutic use, the active compound may be administered orally or directly. Administer enterally, parenterally or topically, preferably orally or topically. It's okay. The therapeutic compositions of the invention may therefore be administered orally, rectally, parenterally or topically. It may take any form of pharmaceutical composition known for therapeutic administration. such a group Pharmaceutically acceptable carriers suitable for use in compositions are well known in the pharmaceutical art. It is being

The compositions according to the invention can contain from 0.1 to 90% by weight of active compound. Composition of the invention The products are generally prepared in unit dosage form. Excipients used in the preparation of these compositions Excipients are excipients known in the pharmacist's art.

Compositions for oral administration are preferred compositions of the invention, and these Pharmaceutical forms for administration, such as tablets, capsules, syrups and aqueous or oily known as suspension. Tablets may contain disintegrants such as corn starch and and lubricants such as lactose or phosphoric acid in the presence of magnesium stearate. Mix the active ingredient with an inert diluent such as calcium and prepare the mixture by known methods. It can be prepared by tabletting. Tablets provide sustained release of compounds of the invention be prescribed in a manner known to those skilled in the art. Wear. If desired, such tablets may be prepared by known methods, e.g. Enteric coating can be provided by using cellulose. Similarly, capsules, For example, hard or Soft gelatin capsules can be manufactured by conventional methods and, if desired, by Alternatively, it may be provided with an enteric coating. Tablets and capsules are conveniently each 0.1 to 5 Contains 00 mg of active compound. Other compositions for oral administration include e.g. If active in an aqueous medium due to the presence of a non-toxic suspending agent such as carboxymethylcellulose, The present invention can be prepared in an aqueous suspension containing a chemical compound, and in a suitable vegetable oil, such as peanut oil. An oily suspension containing a compound of light may also be mentioned.

Compositions for topical administration are also preferred compositions of the invention. pharmaceutically active The compounds can be dispersed in pharmaceutically acceptable creams, ointments or gels. Appropriate Riream is a mixture of petroleum and/or oil dispersed in an aqueous medium using surfactants. by incorporating the active compound into a topical vehicle such as soft liquid paraffin. Can be manufactured.

Ointments contain the active ingredients in mineral oil, petrolatum and/or waxes such as paraphytes. Can be made by mixing with topical excipients such as wax or beeswax . Gels are prepared by combining the active compounds in the presence of water with a gelling agent, such as basicized Carbo It can be prepared by mixing with a topical excipient containing mer B P. applied locally Pharmaceutical compositions also include dispersed pharmaceutically active compounds of the present invention, resulting in A compound is maintained in contact with the skin in order to deliver the compound through the skin. May contain lix. Suitable transdermal compositions include a pharmaceutically active compound and Topical excipients are combined with phase agents such as dimethyl sulfoxide or propylene glycol. It can be produced by mixing together with a transdermal enhancer.

, the compounds of the invention suitable for rectal administration are pharmaceutical forms for such administration. For example, suppositories with semi-synthetic glyceride or polyethylene glycol bases are known. It is being

Compounds of the invention that are suitable for parenteral administration include pharmaceutical forms for such administration. eg sterile suspensions in aqueous and oily media or sterile solutions in suitable solvents. It is being

In some formulations, particles of very small size, e.g. It may be advantageous to use the compounds of the invention in the form of particles, such as those obtained by grinding. It can be done.

In the compositions of the invention, the active compound may, if desired, contain other compatible pharmacological agents. Can be combined with active ingredients.

Compounds of formula I have been indicated for use as immunomodulators, and are generally immunosuppressive agents; Some compounds may exhibit immunostimulant activity in certain disease states . The compounds according to the invention are useful in the treatment of diseases resulting from vagal immune responses. Ru. Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I are therefore suitable for use in immunology. Diseases associated with tissue rejection, such as kidney rejection: rheumatoid arthritis and Autoimmune diseases such as progressive erythema: contact sensitivity, eczema and psoriasis It can be used to treat skin disorders such as skin disorders and neoplasias such as melanoma.

In such treatments, the amount of compound of formula ■ administered per day will determine the therapeutic effect. Generally 0, 1 to 2000 mg, preferably 1 to 500 mg. is within the range of Therefore, in another aspect, the present invention including administering a therapeutically effective amount of a compound of It consists of giving.

The therapeutic activity of compounds of formula I has been demonstrated by standard laboratory animal tests. It's here. Such tests include, for example, its use on BAL B/c mice. Includes oral and parenteral administration of compounds. Thus, compounds of formula I have immunomodulatory properties. It is useful as a nodules drug. However, the exact amount of active compound administered depends on a number of factors. depending on the patient's age, severity of the condition and past medical history; It is within the full discretion of the physician to administer the drug to mammals, including humans. Suitable amounts for oral administration, given in single or divided doses, are generally 0.01- 40 mg/kg/day, more commonly within the range of 0.2-25 mg/kg/day. Ru. For parenteral administration, suitable doses may be given in single or divided doses or is generally administered at a dose of 0.001 to 4.0 mg/kg/day, more commonly by continuous infusion. a, o o Within the range of 5 to 1 mg/kgZ day. Preparations for topical administration are Generally an activity within the range of 0.01 to 20% by weight, more usually 0.05 to 5% by weight. Contains ingredients. Oral administration is preferred.

Next, a method for producing the compound of formula I will be described. These methods form another feature of the invention. to be accomplished.

The compound of formula I has the formula]■ or their tautomers and compounds of the formula [1 [(wherein R14 is (OQ)2 or represents (SQ) 2, R+s represents OQ or SQ or NQ'□, and R 14 represents =NH, RIS represents OQ or SQ, or R14 represents two 〇, R+s represents hydrogen, halo or I-imidazolyl; and Q or and Ql represents a C2-4 alkyl group or a benzyl group). It can be synthesized by

Compounds of formula I are of formula IV (in the formula, R, represents hydrogen), or their tautomers (in the formula, R z represents a group COR,, where R11 is hydrogen, C1-4 alkyl group, benzene or a group R6, Rat represents C0R5, where R5 is of the formula [ ) and a base such as piperidine in a suitable solvent such as ethanol. It can be synthesized by

The compound of formula (2) is R1 and R16 or COR. represents R17 or hydrogen A compound of formula v and a carboxylic acid chloride, such as a substituted benzoyl chloride, are combined with a base, e.g. for example in the presence of triethylamine, followed by a base such as piperidine. It can be synthesized by heating in the presence of water.

where R1 is an alkenyl group or an alkyl group substituted as described herein; Compounds of formula (1) representing a group R1 can be substituted with corresponding compounds of formula I, in which R1 represents hydrogen. , for example, a compound of the formula R+X in which X represents halo and a base, such as sodium hydride. It can be synthesized by alkylation by reacting in the presence of a solvent.

The compound of formula (1) in which R8 represents C2-6 alkanoyl is a compound of formula (3) in which R8 represents hydrogen. The corresponding compounds of formula I can be acylated, for example by reaction with acyl halides. can be synthesized by

Compounds of formula I in which R1 represents cyano are compounds of formula I in which R1 represents hydrogen. For example, in the presence of cyanogen bromide and a base, such as sodium hydride, It can be synthesized by cyanation by reacting with.

Compounds of formula I in which R1 or C2-6 alkoxycarponyl are For substitution of the corresponding compound of formula I with 02-, alkoxycarbonyl group For example, if A is a leaving group, such as cyano or halo, the formula (C2-@alkoxy It can be synthesized by reaction with a compound of (cycarbonyl)A.

A compound of formula I in which R1 represents carbamoylalkyl, e.g. carbamoylmethyl. Compounds of formula I in which R3 represents cyanoalkyl, for example cyanomethyl It can be synthesized by hydrolysis of a compound.

In the formula, R3 is C0NHR. (However, R3° is an easily hydrolyzable group, such as Lolosulfonyl) is a compound of formula I, wherein R3 is hydrogen. By reacting the corresponding compound of I with an isocyanate of formula R2゜N=C=O It can be synthesized more easily. A compound of the formula (■) in which R1 represents carbamoyl is a compound in which R is C0NHR,. For hydrolysis, e.g. acid hydrolysis, of the corresponding compounds of formula I representing It can be synthesized more easily.

Formula I in which R7 is substituted by a carboxylic acid amide group (C0NRjRr) Compounds of A or leaving groups such as hydroxyl, halo, cl-@alkoxy, alkoxy, etc. Ryloxy, arylmethoxy or C1-, a group representing acyloxy -COA, etc. corresponding compounds of formula I which are substituted with alcohols or amines, respectively. (NHR, R, for example, at 0 to 250°C, depending on the case, preferably react in the presence of an organic liquid that is a solvent for the filament and, in some cases, for the reaction. It can be synthesized by reacting in the presence of a catalyst.

Compounds of formula I in which R1 represents a group substituted by a hydroxyl group are s Corresponding formula ■ substituted by an alkanoyloxy group, e.g. acetoxy It can be synthesized by hydrolysis of a compound.

A compound of formula (3) in which R1 is substituted with a C21 alkanoyloxy group is can be synthesized by acylation of the corresponding compound of formula I substituted by a drooxy group .

Compounds of formula [I are of formula V It can be synthesized by reacting the compound with hydrazine of the formula H=NNHR+ .

Compounds of formula III in which R14 or (OQ), and RIM represents OQ, are For example, a) a compound of formula R5CX1 in which X is halo and a compound of formula R5CX1 in which Q is C1-4 alkyl; reacts with a sodium alkoxide of formula Na0Q, which is a benzyl group or a benzyl group. or b) Equation 1? , CN and an alcohol of formula QOI ( A compound of the formula R,C(=NH)OQ as an acid anhydride, e.g. its acid salt, e.g. hydrochloride; are reacted in the presence of hydrogen chloride to yield the compounds, which are then reacted with another alkali of formula QOH. It can be synthesized by reacting with kohl.

Compounds of formula IV, in which R26 or COR, represents Rat or CORs, are , where R1g represents COR1g and R17 represents hydrogen, By acylation, for example, the formula ( R8CO)20 acid anhydride, or acid halide in the presence of a base such as triethylamine. It can be synthesized by reaction with a halogenide such as RjCOCI.

In the formula, R1, or CUR, is represented by a formula in which RIT represents hydrogen [the compound of V is a formula Acylation of compounds of [[, e.g. salts of the corresponding acids (e.g. sodium salts)] It can be synthesized by reaction with an acid anhydride of formula (R1,C0)tO in the presence of .

A compound of the formula [■, where RlT represents C0R6 and Rlg represents hydrogen, or These tautomers have the formula where R16 represents COR, and R1□ represents COR. A compound of formula V and a base such as piperidine are combined in a suitable solvent such as ethanol. It can be synthesized by reacting it in a tank.

where R1 and R1, represent R11 or COR+s as defined above; Compounds of formula IV in which R1□ represents hydrogen, compounds of formula The compound and the acid anhydride of formula (R,,C0)20 are combined into a salt of the corresponding acid (e.g. sodium It can be synthesized by reacting in the presence of salt).

Compounds of formula V are of formula Vl (In the formula, R22 represents hydrogen) and malonic acid are combined into an acid chloride, e.g. Synthesis is achieved by reaction in the presence of phosphoryl and a Lewis acid, such as zinc chloride. Can be done.

A compound of formula V is a compound of formula v1 in which R2) represents an acetyl group and a base, e.g. represents sodium hydride, and Q in the formula represents an alkyl group or a benzyl group. Reacting with a dialkyl carbonate of the formula (QC) 2CO, such as dimethyl carbonate. It can be synthesized by

Compounds of formula V in which R4 or 01-6 alkoxy represent R4 or halo, e.g. a compound of formula Vl in which R18 represents fluoro and R18 represents an acetyl group and a base; , for example sodium hydride, and where Q is a CI-4 alkyl group or benzyl Formula (QC) representing a group, synthesized from carbon dialkyl of CO, for example dimethyl carbonate Can be done.

Certain intermediate compounds of 2 [L [rr], IV, ■ and ■1 are new compounds. I believe that it is. All novel compounds herein are considered as separate aspects of the invention. A patent is claimed.

The invention is illustrated by the following non-limiting examples. In the examples, parts and percentages are by weight. The composition of the mixed solvent is shown by volume. Characteristics The process includes elemental analysis and the following spectroscopic techniques: nuclear magnetic resonance, infrared spectroscopy and mass spectroscopy. a) 2'-fluoro-6'-hydroxyphenyl henone (30 g) in dry toluene (400 ml) with sodium hydride (17, 1 g, 60% dispersion in mineral oil) over 30 minutes. and boiled under nitrogen under reflux. After boiling, add diethyl carbonate (5o, 8 g) in a dropwise manner over 10 minutes and continued heating for a further 20 minutes. did. The resulting mixture was stirred and heated under reflux for 20 hours. Circulate the reaction mixture. It was cooled to ambient temperature and water (150 ml) was added dropwise. After separation, the aqueous phase is evaporated. ether and then acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and washed with water. After washing, drying and recrystallization from ethyl acetate, 5-ethoxy-4-hydroxy Coumarin, melting point 110-+11°C was obtained.

Example 2 4-Hydroxycoumarin (10,0 g) in dry toluene (50 ml), Shu Acid ethylhydrazine (14,25g) and triethylamine (24,0ml) The stirred mixture of was heated under reflux for 3 hours without removing the water formed during the reaction. did. The solids collected after filtration were partitioned between water and dichloromethane. Dry the organic layer and evaporated to give a solid which was recrystallized from butanol to give 1-ethyl-3-(2 -hydroxyphenyl)-2-pyrazolin-5-one, melting point 147-150°C I got it.

Example 3 Hydrazine (32.3 g) was dissolved in 4-hydrohydrazine in absolute alcohol (1.2 liters). Dropwise into a stirred solution of xycoumarin (50,0 g) for a period of 0.25 hours. The reaction mixture was stirred for 20 hours and then heated to reflux.

The solution was cooled, acidified with glacial acetic acid (154 ml) and the ethanol was evaporated under reduced pressure. The oil was removed and poured into water (1.5 liters). resulting The solid was filtered off, washed with water, dried and recrystallized from isopropanol to give 3-(2 -hydroxyphenyl)-2-pyrazolin-5-one, melting point 205-207°C Obtained.

Examples 4-6 In a manner similar to that described in Example 3, a compound of formula Formula H2NNHRI, where the substituents R4 and R3 are summarized in the table below: It was synthesized by reacting with hydrazine.

Example 7 4-triflu in dry ether (120ml) and dry methanol (6ml) A solution of olomethylbenzonitrile (25 g) was cooled to 0-5°C and diluted with hydrogen chloride. Saturated with gas. The reaction mixture was left in a melt water bath overnight to precipitate the imide salt. was collected by filtration, washed with ether and dried in a desiccator. this solid was added to AR methanol (78.3 ml) without stirring and the mixture was heated at ambient temperature. Stirred for 5B. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give trimethylol. (4-trifluoromethylbenzoate) was obtained as an oil without further purification. used.

Example 8 a) 4-Hydroxy-5-methoxy in industrial methylated spirit (84 ml) A mixture of coumarin (4.0 g) and hydrazine hydrate (3.0 ml) was heated under reflux. The mixture was boiled for 4.75 hours. After cooling, add glacial acetic acid (13.3 ml) and The filtrate was removed under reduced pressure. Add the residue to water and dissolve the separated gum in a small amount of dichloromethane. Solidification occurred upon addition of tungsten. The solid was collected by filtration and 3-(2-hydroxy -6-Medoxyphenyl)-2-pyrazolin-5-one, melting point 208-210° I got a C.

b) 3-(2-hydroxo-6-medoxyphenylene) in dry xylene (50...1) )-2-biraprin-5-one (2,06 g) and I-(4-trifluoro A mixture of methyl-benzoyl)imidazole (5.04 g) was stirred and brought to reflux. and nitrogen for 0.5 hour and then cooled to ambient temperature. Filter the solid produced and then boiling industrial methylated spirit/dichloromethane (1,2 ) dissolved in The dichloromethane was boiled off until the solid separated. mixture Cool to ambient temperature and filter to remove 9-methoxy-4-(4-)lifluoromethyl fluoride. C) Sodium hydride (0,114g, 60% dispersion in mineral oil) in dry N,N- 9-methoxy-4-(4-1-refluorinated) in dimethylformamide (55 ml) 2-bromoethyl ethyl ether (0,36 m1190%) was added dropwise followed by stirring at ambient temperature for 16 hours. blend was added to water containing a small amount of petroleum ether (boiling point 62-68°C). blend Acidified with 2M hydrochloric acid and filtered to give 2-(2-ethoxyethyl)-9-methoxy- 4-(44lifluoromethyl-phenyl)[1]benzopyrano(4,3-c)pi Lazol-3(2H)-one, melting point 164-168°C was obtained.

a) 5-Ethoquino-4-hydrocuma in industrial methylated spirit (60 ml) A mixture of phosphorus (5.0 g) (Example 1) and methylhydrazine (2.2 g) was Heated under reflux for 20 hours. After cooling, the solvent was evaporated off under reduced pressure to obtain the crude product. Obtained. Methanol (50 ml) and concentrated hydrochloric acid (20 ml) were added to the crude product. and the resulting solution was heated under reflux for 2 hours. After evaporation of the solvent under reduced pressure, The residue was triturated with water and the resulting solid was collected by filtration and dried to give 3-(2-hydrohydride). Roxy-6-ethoxyphenyl)-1-methyl-2-virapurin-5-one was obtained. Ta.

b) The solid obtained in (a) above (3.2 g) and trimethylortho(4-talo) Lobenzoe) (9.0 g) was heated together at 130-140°C for 45 minutes. . The mixture was cooled to ambient temperature and hegyusan (50 DI) was added.

The supernatant was decanted and ether (80 ml) was added to the remaining oil to dissolve the solid. was precipitated. The solids were collected by filtration, washed with ether, dried, and then purified. Recrystallized from ropan-2-ol to give 4-(4-chlorophenyl)-9-ethoxy -2-Methyl[1]-benzopyrano[4゜3-c]pyrazole-3(2H)- On, a melting point of 197-199°C was obtained.

Example 1O a) 4-hydroxycoumarin (3,6 g) and 2, in toluene (27 ml) 2. A mixture of 2-trifluoroethylhydrazine (5.0 g) was prepared without removing the water. The mixture was heated under reflux for 4 hours. After cooling and filtration, the collected solids were dissolved in hot dichloromethane. Extracted with water, filtered and the filtrate was evaporated.

The solid product was recrystallized from toluene and then dichloromethane to give 3-(2-hydroxy Cyphenyl)-1-(2,2゜2-trifluoroethyl)-2-pyrazoline-5 -one, melting point 163-165°C was obtained.

b) The solid obtained in (a) above (1.2 g) and trimethylortho(4-chlorobenzene) (3.0 g) was heated together at 125° C. for 10 minutes. Cool the mixture Cooled, diluted with ether (loml), and the resulting solid was dissolved in N,N-dimethylform. Recrystallized from a mixture of amide and methanol to give 4-(4-chlorophenyl>-2 -(2,2,2-trifluoroethyl)[l]benzpyrano(4,3-c)-pi Lazol-3(2H)-one, melting point 214-215°C (decomposition) was obtained.

Example 11 a) 3-(2-hydroxyphenyl)-1-methyl-2 synthesized in Example 4 -Pyrazolin-5-one (3°8g), anhydrous sodium acetate (1.64g) and A mixture of acetic acid and acetic anhydride (30+nl) was stirred at ambient temperature for 1.5 hours.

The reaction mixture was added to water (10 volumes) and extracted with ethyl acetate. Combined organic extraction The extract was washed with water, dried and evaporated. The semi-crystalline residue was dissolved in petroleum ether (boiling point 60 The solids were collected by filtration and dried to give 3-(2-hydroxy Cyphenyl)-1-methyl-5-virazolyl acetate, melting point 113-116° I got a C.

b) 3,4-dichlorobenzoyl chloride ( A solution of 4.4 g) was added to tetrahydrofuran (100 ml) and and 3-(2-hydroxyphenyl)=1-methylene in triethylamine (3 ml). (4,5 g) at 0-5°C. added. The mixture was stirred at ambient temperature for 18 hours, then further treated with tetrahydrofuran. 3,4-dichlorobenzoylene in (80 ml) and triethylamine (3 ml) chloride (4.4 g) was added. After stirring for an additional 24 hours, the reaction mixture was dissolved in water (1 The mixture was poured into a liter bottle and extracted with ethyl acetate. Dry the combined organic extracts. , and then concentrated until a precipitate formed. To remove 3,4-dichlorobenzoic acid After filtration, the filtrate was evaporated under reduced pressure and the residue was crystallized from ethyl acetate to give 2-(5-alcohol). Setoxy-1-methyl-3-pyrazolyl)phenyl 3,4-dichlorobenzoate A melting point of 123°C was obtained.

c) 2(5-acetoxy-1-methyl-3-pyrazolyl)phenyl 3,4-di Add chlorohenshade (1.0 g) and piperidine (0.27 ml) to ethanol. The mixture was heated under reflux for 2 hours in a bottle (10 ml). Cool the reaction mixture to 0°C. Ta. The product was collected by filtration and recrystallized from ethanol to give 4-(3,4-ink). lorophenyl)-2 Example 12 a) 3 synthesized in Example 11a in dry tetrahydrofuran (50 ml) -(2-hydroxyphenyl)-1-methyl-5-pyrazolylacetate (2, A solution of 32 g) was subsequently dissolved in triethyl chloride in dry tetrahydrofuran (10 ml). (1,5 ml) and 2-naphthoyl chloride (2,1 g) at 0-5°C. Ta. The mixture was stirred at ambient temperature for 20 hours and then further treated with triethylamine (0, 75 ml) and 2-naphthoyl chloride (1,05 g) and the mixture was further stirred. The mixture was stirred for 20 hours. The reaction mixture was poured into water (10 volumes) and diluted with ethyl acetate. Extracted. The combined organic extracts were washed with saturated sodium carbonate solution, then water, then washed with It was dry. After evaporation under reduced pressure, triturate the residue with ether and filter the resulting solid. Collected by.

b) A portion of the crude solid from step (a) (2,43 g) and piperidine (0,63 m 1) was boiled in absolute ethanol (19 ml) under reflux for 30 minutes. After cooling , the mixture was filtered to give 2-(l-methyl-5-oxo-4,5-dihydro-3-pi Lazolyl) phenyl 2-naphtonite was obtained, melting point 207-210''C.

C) The filtrate was boiled under reflux for a further 1 hour. The mixture was concentrated and then cooled. Ta. The resulting solid was collected by filtration to obtain 2-methyl-4-(2-naphthyl) [l ]Benzopyrano(4,3-c)pyrazol-3(2H)-one, melting point 159~+ 61″C was obtained.

Example 13 3-(2-hydroxyphenyl)-2-bilaprin-5-one (2,32 g) and triethylortho(4-chlorobenzoate) (10.2 g) in a stirred solution of The mixture was heated at 130-135°C for 1 hour. Cool the mixture to ambient temperature, Diluted with ether and the resulting solid was filtered off, washed and dried. machining solids Recrystallized from commercial methylated spirit (using charcoal) to give 4-(4-chlorofluorophore). (benzyl)[l]benzopyrano(4,3-c) as described in Example 13 In a similar manner, a compound of formula I can be prepared by combining a compound of formula fr with a substituent R of R4 is synthesized by reacting with a compound of the formula [[[ as summarized in Table B below. Ta. The compounds of formula frI used represent R2 or hydrogen, R2 and Q as shown in Table B. There was a type of R=C(OQ)a shown.

Example 19 3-(2-hydroxyphenyl)-2-pyrazoline in xylene (200ml) -5-one (16 g) and 1-(4-chlorobenzoyl)imidazole (37 , 5g) was stirred and heated under reflux for 3 hours. Heat the mixture to 70°C. Allow to cool and then filter to obtain 4-(4-chlorophenyl)[l]-benzopyrano. (4,3-c)pyrazol-3(2H)-one, melting point 255-257°C Trimethylortho(4-trifluoromethyl-benzoate) synthesized in Example 7 ) (5,5 g), and 3-(2-hydroxyphenyl)-2-virapurin-5 -one (1.94 g) was heated at 135-140° C. for 4 hours. mixture The solid produced was filtered off and washed with ether. Grind with hot water and filter to obtain 4-(4-trifluoromethylphenyl)3-(2-hyperoxyphenyl). droxyphenyl)-2-pyrazolin-5-one (30.2 g), 1-(4-t Lifluoromethylbenzoyl)imidazole (86,5 g) and xylene (8 The mixture was stirred and boiled under nitrogen for 4 hours under reflux. reaction mixture The mixture was cooled to 40°C and filtered to give 4-(4-trifluoromethylphenyl). [1] Benzopyrano(4,3-c)-pyrazol-3(28)-one, melting point 27 0-272°C was obtained.

Example 22 a) 3-(2-hydroxyphenyl)-2-pyrazo in acetic anhydride (30n+1) A mixture of phosphorus-5-one (3,52 g) and sodium acetate (1,64 g) Stirred at ambient temperature for 3 hours. Mix water and petroleum ether (boiling point 62-68°C1) IO:I) and collect the solid by filtration to obtain the crude l-acetyl-3-( 2-hydroxyphenyl)-5-pyrazolylacetate, melting point 62-64°C Obtained.

b) Crude l-acetyl-3-(2-hydroxyphenyl)-5-pyrazolylacetate tate (1,53 g), triethylamine (2,1 ml) and dry tetrahydride A mixture of lofuran (25 ml) was mixed with 4-trifluoromethylbenzoyl chloride (3 , 21 g) was added dropwise and then stirred at 0-5°C. The resulting confusion The mixture was stirred at ambient temperature for 64 hours and then poured into water. The product was converted into ethyl acetate. the combined extracts in water, saturated sodium bicarbonate solution and finally in water. Washed with. After drying, the solvent was evaporated off under reduced pressure. Heat the residue in propane-2-O Digested in a boiler, then cooled and filtered. The filtrate was evaporated to give the crude 2-(5-aceto xy-1-acetyl-3-pyrazolyl)phenyl 4-trifluoromethylbenzo The ate was obtained as an oil.

C) The oil from step (b) and piperidine (0.7 ml) were dissolved in anhydrous ether under reflux. Boiled in Nord (22 ml) for 1 hour. Cool the mixture to 0-5°C, The crude product was then filtered and dichloromethane/methanol ( Purified by preparative layer chromatography on silica gel using 4-(4-trifluoromethylphenyl)[l]benzopyranoC4,3-C]py Lazol-3(2H)-one, melting point 268-272°C was obtained.

Example 23 3-(2-hydroxyphenyl)-2-pyrazo in dry xylene (30011) A mixture of phosphorus-5-one (2,9 g) and potassium carbonate (3,2 g) was stirred. , 4-trifluoromethylbenzoyl chloride (6,9 g) over 15 minutes. Heat to reflux while adding dropwise.

The mixture was boiled and stirred for 2 hours, then filtered hot.

The collected solids were washed with toluene, water and finally ether to obtain 4-(4-tritrifluoride). fluoromethylphenyl) [1] benzopyrano (4,3-c) pyrazole-3 (2H)-one, melting point 259-263°C was obtained.

Example 24 3-(2-hydroxyphenyl)-1-methyl-2-pyrazolin-5-one (real Example 4) (1,90 g) was dissolved in hot toluene (100Q11) and then in dry toluene (5oml) containing piperidine (1ml). of 4-chlorobenzoyldehyde (1.4 g) during the reaction. The water produced was removed and added over a period of 5.25 hours. reaction mixture Evaporate under reduced pressure, triturate the residue with ether and recrystallize from propan-2-ol. 4-(4-chlorophenyl)-2-(2-chloroethoxy)ethyl acetate (16°7g), sodium bromide (103g), N,N-dimethylformamide The mixture (200ml) was stirred and heated at 100°C for 48 hours. Mixture of water (300 ml) and water (200 ml). Separate the remaining organic layer , washed with water, dried and evaporated to give an oil. 2-(2-butyl) by distillation under reduced pressure. Lomoethoxy) ethyl acetate, boiling point 100-103 °C (7 mmHg) was obtained. Ta.

Example 26 Sodium hydride (0.60 g, 50% dispersion in mineral oil) was dissolved in dry N,N-dimethylene 4-(4-chloroformamide) synthesized in Example I3 in chloroformamide (145 ml). It was added under Rofe. The mixture was stirred at ambient temperature for 5 minutes, then 2-bromoe Thilacetate (1.38 ml) was added dropwise. Bring the reaction mixture to ambient temperature for 16 hours, then water and gasoline (boiling point 60-80°C: approx. 0:I volume). The mixture was cooled in a water bath and the precipitated solid was filtered off. , washed to give 2-(4-(4-chlorophenyl)-3-year-old xo-2,3-dihyde) rho-(1)benzopyrano(4,3-c)pyrazol-2-yl]ethyl acetate A melting point of 126-129°C was obtained.

Examples 27-41 In a similar manner to Example 26, the compound of formula I was prepared as 4-(4-chlorophenyl)CI] BenzopyranoC4,3-c)pyrazol-3(2H)-one (A) (Example 3) and X are halogens as summarized in Table C below; and Synthesized by reaction.

Treated with charcoal and filtered. The filtrate is evaporated, the residue is triturated with gasoline and filtered to produce raw A product was obtained.

(7) The reaction mixture was quenched in water (300 ml) containing 2M hydrochloric acid (5 ml). , extracted with dichloromethane. The combined extracts were dried and evaporated. A The mixture was partitioned between water and water and then separated. Extract the aqueous layer with ether and combine the ether The extract was dried and concentrated (to 10 ml). Collect the generated solid by filtration. The mixture was collected, washed with petroleum ether (boiling point 40-60°C), and dried. from ethanol After recrystallization of the product, dichloromethane/methanol, 98:2 was used as the mobile phase. Purified by flash chromatography on silica used. eluted The material was recrystallized from ethanol to give the product.

(8) The reaction mixture was partitioned between 5M hydrochloric acid (600ml) and ether (300ml). Ta. The aqueous layer was separated and washed with ether. Dilute the combined ether extracts with water. Washed for minutes, dried and evaporated. Dichloromethane/methanol was used as the mobile phase. Purified by flash chromatography on silica using 97:3 Ta. The resulting solid was recrystallized twice from a mixture of ether and ethyl acetate to give the product. Obtained.

(10) The reaction mixture was added to water and acidified with 5M hydrochloric acid.

The solid was collected by filtration and recrystallized from N,N-dimethylformamide.

(11) The reaction mixture was added to water. The resulting solid was collected by filtration and It was recrystallized from ion-2-ol.

(12) A 60% dispersion of sodium hydride in mineral oil was used.

(13) The reaction mixture was added to water (500ml) and extracted with ether. Matching The extracts were washed with water, dried and evaporated. The resulting solid was reconsolidated from ethanol. crystallized.

(14) Add the reaction mixture to water (2 liters), acidify with 5M hydrochloric acid, and Extracted with chill. The combined extracts were washed with water, dried and evaporated. the resulting oil was crystallized from ether.

Example 42 In a similar manner to Example 26, sodium hydride (0.74 g, 60% in mineral oil) powder), dry N,N-dimethylformamide (180ml), 4-(4-k) surrounding a mixture of lorophenylomomethyl-1,3-dioxolane (1,97 ml). Stir at temperature for 16 hours. Add sodium hydride (0.74g) little by little. Then, 2-bromomethyl-1,3-dioxolane (1,97ml) was added. Added. The mixture was stirred at ambient temperature for 24 hours, then at 70-80'C for 1 hour. Warmed. The mixture was cooled to ambient temperature and then added to water. The solid produced Collected by filtration, dried and recrystallized from ethanol/dichloromethane to give 4-( 4-chlorophenyl)-2-(1,3-dioxolan-2-ylmethyl) [l] Henzopyrano [4,3-c)pyrazol-3(2H)-one, melting point 230-2 31°C was obtained.

Example 43 Sodium hydride (0.44 g, 6096 in mineral oil) was prepared in a similar manner to Example 26. dispersion), dry N,N-dimethylformamide (I O0ml), 4-(4 -chlorophenyl) [1] benzopyrano [4,3 once] pyrazole-3 (2H )-one (3,0 g) (Example 13) and l-bromo-2-ethoxypropane A mixture of (2.9 g) was stirred at ambient temperature for 16 hours. The mixture was heated at about 60°C 1. Warmed for 5 hours then cooled to ambient temperature. Add the mixture to water and add the product to the water. Extracted into tel. The combined ether extracts were dried and evaporated. Transfer the residue to the mobile phase Ethyl acetate/petroleum ether (boiling point 80-100 °C) (1:3) is used as Separated by flash chromatography on silica to obtain a red solid; This was recrystallized from ethanol to give 4-(4-chlorophenyl)-2-(2-ethoxy). Cypropyl) [1] Benzopyrano C4,3-c) Billa Method similar to Example 26 Sodium hydride (1.82 g, 60% dispersion in mineral oil), dry N,N-di Methylformamide (450ml), 4-(4-trifluoromethylphenylphenyl) ) [l] Benzopyrano [4,3-c) pyrazol-3(2H)-one (15 ,0g) (Example 20) and 2-bromoethyl acetate-1-(7,62g). The mixture was stirred at ambient temperature for 48 hours. The mixture was added to water. solid produced was filtered off, dissolved in ethyl acetate, and washed with water. Removal of ethyl acetate under reduced pressure After evaporation, the obtained residue was recrystallized from propan-2-ol to give 2-[3-oxo- 4-(4-trifluoromethylphenyl)-2,3-dihydro[1]benzopyra No.C4,3-34-136°C was obtained.

Example 45 In a similar manner to Example 26, sodium hydride (0.74 g, 60% in mineral oil) powder), dry N,N-dimethylformamide (150 ml), 4-(4-k) lorophenyl)[1]benzopyrano[4,3-[]pyrazol-3(2H)-o (5,0 g) and 2-(2-bromoethyl)-1,3-dioxane (2,5 2m! ,) was stirred at ambient temperature for 42 hours. The reaction mixture was added to water .

The product was extracted into a needle and the extract was washed with water.

Evaporation of the ether leaves a solid residue, which is recrystallized from ethanol to give 4-( 4-chlorophenyl)-2-(2-(1,3-dioxan-2-yl)ethyl] [1] Benzopyrano[4,3-c)pyrazole-3 (2 Example 46 2-[3-year-old xo-4-(4-trifluoromethylphenyl)-2,3-dihyde B [1) Benzopyrano [4゜3 once] pyrazol-2-yl] ethyl acetate (17.93 g) (Example 44), 2M hydrochloric acid (22 ml) and industrial methyl A mixture of distilled spirits (750ml) was stirred and boiled under reflux for 18 hours.

The mixture was cooled to 0°C and the solid produced was collected by filtration and Droxyethyl)-4-(4-trifluoromethylphenyl)[l]Henzovira No(4,3-c) pyrazol-3(2H)-one, M point 199-201″C Obtained.

Example 47 Dilute hydrochloric acid (2 ml) in industrial methylated spirit (80 ml) in Example 26. The synthesized 2-(4-(4-chlorophenyl)-3-year-old xo-2,3-dihydrogen) Doro[1]benzopyrano(4,3-c)pyrazol-2-yl]ethyl acetate (1.53 g) at ambient temperature. Also reflux the mixture. and heated for 6.5 hours. The solution was allowed to cool and kept at ambient temperature for 16 hours.

The resulting crystals were filtered off and washed with industrial methylated spirits to give 4-(4- chlorophenyl)-2-(2-hydroxyethyl)-(1) benzopyrano C4, 3-3-(4-(4-chlorophenyl)-3-oxo-2°3-dihydro [1) Benzopyrano(4,3-c)pyrazol-2-yl]propyl acetate (1, 5g) (Example 41), 2M hydrochloric acid (1.9ml) and industrial methylated spirit. The mixture was boiled under reflux for 5 hours. Cool the mixture to room temperature The solid produced was collected by filtration to give 4-(4-chlorophenyl)-2-( 3-hydroxypropyl)[1]benzopyranoC4,3-C]pyrazole-3 (2H)-one, melting point 166-168°C was obtained.

Example 49 2-(2-(4-(4-chlorophenyl)-3-oxo-2,3-dihydro( 1) Benzopyrano (4,3-C]pyrazol-2-yl]ethoxy)ethyl a Cetate (l1g) (Example 39), 5M hydrochloric acid (100ml) and water (100ml) +nl) mixture was stirred and boiled under reflux for 24 hours. Evaporate the mixture; The obtained solid was recrystallized from propan-2-ol (100[111) to give 4-( 4-chlorophenyl)-2-(2-(2-hydroxyeth).

Example 50 4-(4-chlorophenyl)-3-year-old xo-2,3- synthesized in Example 28 Dihydro (1) benzopyrano (4,3-c) pyrazole-2-acetonitri (0.68g) and concentrated sulfuric acid (6ml) at 120°C for 0.5 hours. It was heated for a while. Pour the reaction mixture onto ice (10 volumes) and collect and wash the solid product. and dried to give 4-(4-chlorophenyl)-3-year-old xo-2,3-dihydro(1 ] Henzopyrano(4,3-c)pyrazole-2-acetamide, melting point 279-28 3°C was obtained.

Example 51 4-(4-chlorophenyl synthesized in Example 32 in the same manner as in Example 50) )-3-oxo-2,3-dihydro [1) benzopyrano [4,3-c) birashi -Mixture of 2-propionitrile (1,0g) and concentrated sulfuric acid (10ml) Heat the material to 120-125°C for 15 minutes and reconstitute it from industrial methylated spirit. After crystallization, 4-(4-chlorophenyl)-3-oxo-2,3-dihydro(1)ben Zopyrano C4,3-c) Pyrazole-2-propionamide, melting point 264-26 6°C was obtained.

Example 52 a) 4-(4-k) synthesized in Example 31 in dichloromethane (50 ml) lorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano (4,3 -c) Dry the stirred suspension of pyrazole-2-acetic acid (2,16 g) with N,N -dimethylformamide (0.24ml), then thionyl chloride (1.51ml) l). The mixture was stirred at ambient temperature for 16 hours and then evaporated under reduced pressure. I set it.

Triturate the residue with dry ether and collect the solid by filtration to obtain 4-(4-chlorophene). nyl)-3-oxo-2,3-dihydro(1)benzopyrano C4,3-c) Pyrazole-2-acetyl chloride was obtained.

b) of this acid chloride (1,08 g) in dry tetrahydrofuran (100 ml) A portion was treated with an aqueous ethylamine solution (0.43 ml 1.70% W/W) in a dropwise manner. Ta. The mixture was stirred at 0-5°C for 1.5 hours and then filtered. Pour the filtrate into ether ( 100 ml), cooled in a water bath for 3 hours and filtered off the solid. After leaving it for a few days , obtained another group of solids.

The two combined groups were washed with water and then with petroleum ether (boiling point 60-80°C). 4-(4-chlorophenyl)-N-ethyl-3=oxo-2,3-dihydro[ 1] Benzopyrano C4,3-c] pyrazole-2-acetamide, melting point 238-2 39°C was obtained.

Example 53 In a similar manner to Example 52(a), 4-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano C4,3-c) pyrazole-2-acetic acid ( 1,87 g) in acid chloride (1,89 g) and then in dry tetrahydrofuranate. Suspended in run (172[+11) at 0-5°C.

Add aqueous methylamine (0,690] L 25/30% W/V) in a dropwise manner. and the mixture was stirred in a melt water bath for 2.5 hours. Filter off the solids, add water and then evaporate. -2,3-dihydro[1]henzopyranoC4,3-c)pyrazo Sol-2-acetamide, melting point 244-250°C, was dissolved in dry tetrahydrofuran (1 A solution of propylamine (0.2 ml) in 4-(4-chlorophenyl)-3-year-old xo2,3 in dorofuran (95 ml) -dihydro[1]benzopyrano(4,3)pyrazole-2-acetyl chloride (1,07 g) (Example 52a) was added with stirring at 0-5°C. . The mixture was stirred for 50 min at 0-5 °C and then further treated with dry tetrahydrofuran. Propylamine (0.1 ml) in (5 ml) was added. Add this mixture to 0-5 Stir for 2.3 h at °C, then dilute with dry ether (951111) and The mixture was stirred at 5°C for 1 hour. The mixture was filtered, the filtrate was washed with water, dried and dried under reduced pressure. evaporated with. The residue was used as the mobile phase in dichloromethane and then in dichloromethane/methane. Separation was performed on a Florisjl column using ethanol (95:5). profit The resulting solid was triturated with ether to give 4-(4-chloro2-acetamide, melting point 218~ 223°C was obtained.

Example 55 4-(4-chlorophenyl)H)-one in toluene (20 ml) (Example 13) ) (1,0 g) was mixed with a stirred mixture of (chlorosulfonyl isocyanate) (0,5 3 g) at ambient temperature. Heat the mixture to 70’C and keep at this temperature for 15 minutes. Stir for a while. After cooling to 0°C, the mixture was filtered and the residue was washed with ether. The mixture was suspended in glacial acetic acid (6 ml) and water (3 ml). Heat this mixture to 60°C Heat for 15 minutes then filter. Wash the residue with water, dry and dichloromethane. /methanol, recrystallized from 41 to give 4-(4-chlorophenyl)-3-year-old xo 2.3-dihydro[1]benzopyrano(4,3-c)pyrazole-2-carboxy Cyamide, melting point 215-216°C was obtained.

Example 56 Acetyl chloride (0.86 ml) was dissolved in 4-(4-chloride) in AR acetone (20 ml). lophenyl)[l]benzopyrano(4,3-c)pyrazol-3(2H)-one Example 13 A stirred mixture of (3.0 g) and potassium carbonate (2.79 g) The mixture was added dropwise at ambient temperature. The mixture was stirred at ambient temperature for 42 hours. . More potassium carbonate (6°98g), followed by more AR acetone (15ml) of acetyl chloride (3.6 ml) was added. Stir the mixture at ambient temperature for 18 hours. did. Additionally, potassium carbonate (2,79 g) and acetyl chloride (1,44 ml) was added and the mixture was stirred at ambient temperature for 2.25 hours. The mixture is then brought under reflux. Boiled for 1 hour, cooled to ambient temperature, then added to water. solid produced was collected by filtration, dried, and then recrystallized from acetonitrile to give 2-acetyl Ru-4-(4-chlorophenyl)[1]henzopyrano[4°3-c]pyrazole -3(2H)-one, melting point 224-226°C was obtained.

Example 57 4-(4-chlorophenyl)[l]benzopyrano[4゜3-c]pyrazole-3 (2H)-one (Example 13) (20 g) and ethyl chloroformate (20 The stirred mixture of 0a+1) was boiled under reflux for 5 hours. Furthermore, Ethiluk Roloformate (50ml) was added and the mixture was stirred and boiled under reflux for 4 hours. I let it happen. The reaction mixture was cooled to ambient temperature, the solids collected by filtration and washed with acetonate. Recrystallized from tolyl. The obtained crude product was dichloromethane/methane as the mobile phase. by flash chromatography on silica using ethanol (9:1). and purified. Evaporation of the eluent gave a solid which was recrystallized from ethyl acetate. Chyl 4-(4-chlorophenyl)-3-xo-2,3-dihydro(1)benzo Pyrano[4°3-c]pyrazole-2-carboxylate, melting point 187-188 ℃ was obtained.

Example 58 4-(4-chlorophenyl)[1]benzopyrano[4゜3-c]pyrazole-3 (2H)-one (Example 13) (5 g) and ethyl cyanoformate (50 m The stirred mixture of l) was boiled under reflux for 3.5 hours. Surrounding the reaction mixture Cool to temperature, dilute with petroleum ether (30 ml), filter and dry ethyl 4-(4-chlorophenyl)-3-year-old xo-2,3-dihydroC1)benzopyra No(4,3-c)pyrazole-2-carboxylate, melting point 187-189°C I got it.

Example 59 4 synthesized in Example 52(a) in dry tetrahydrofuran (76 ml) -(4-chlorophenyl)-3-year-old xo-2,3-dihydro(1)benzopyrano [4°3-C]pyrazole-2-acetyl chloride (0.97g) was stirred A suspension of cyclobutanol (0, 7 g) followed by triethylamine (0.35 ml). the result The above mixture was stirred at ambient temperature for 2.67 hours and then filtered. Ether the filtrate diluted with water, washed with water, dried and then evaporated under reduced pressure. The residue is used as the mobile phase. Preparative phase chromatography on silica using dichloromethane/methanol (9:I) Purified by matography. High speed running band (run old B band ) was extracted with ethyl acetate. Obtain the gum by evaporation under reduced pressure and convert it into ether / triturated with petroleum ether (boiling point 62-68°C, 1:1) and filtered to obtain cyclobutyl 4-(4-chlorophenyl)-3-oxo-2,3-dihydro(1)benzopi Lano (4,3-C]pyrazole-2-acetate, melting point 135-138°C Obtained.

Example 60 Sodium hydride (0.48 g, 60% dispersion in mineral oil) was dissolved in dry N, N-dimethyl 4-(4-1- Added to refluorofluid under nitrogen. The mixture was stirred at ambient temperature for 0.5 h, then Bromoacetonitrile (1.46 g) was added to No-4. Bring the mixture to ambient temperature Stirred for 18 hours then added to ice water. The mixture was extracted with ethyl acetate and combined. The extracted extract was washed with water, dried, and evaporated to obtain a solid, which was transferred to a propatool. Recrystallized from 3-year-old xo-4-(4-trifluoromethylphenyl)-2,3- dihydro(1)benzopyrano(4,3-C)pyrazole-2-a7tonitrile, A melting point of 215-217°C was obtained.

Example 61 In a similar manner to Example 60, 4-(4-1 lifluorome (0.21 g, in mineral oil) was prepared. 50% dispersion), 2-bromoethyl ethyl ether (0,77 g) and dry N , N-dimethylformamide (50 ml) and stirred at ambient temperature for 42 hours. Ta. The resulting crude product was flashed on silica using ethyl acetate as the mobile phase. Purified by column chromatography and reconsolidated from propan-2-ol. After crystallization, 2-(2-ethoxyethyl)-4-(4-trifluoromethylphenyl) [l]Benzopyrano[4,3]pyrazol-3(2H)-one, melting point 126 ~128°C was obtained.

Example 62 2-(2-hydroxyethyl)-4-(4-trifluoro synthesized in Example 46) (romethylphenyl) [1] benzopyrano [4,3 once] pyrazole-3 (2 and) -Oniz (8.22g) and 48% hydrobromic acid water (500ml) were stirred and reduced. Heated for 28 hours under flowing water. The reaction mixture was cooled to 0°C and the solid was collected by filtration. It was collected, washed with water, dried, and recrystallized from acetonitrile. lomoethyl)-4-(4-trifluoromethylphene a) Method similar to Example 60 and 4-(4-) rifrum (0.7 g, 60% dispersion in mineral oil), ethyl 4-butylene Lomobutyrate (2,4 ml) and dry N,N-dimethylformamide (23 0 ml) and stirred at ambient temperature for 24 hours. The reaction mixture was mixed with water (2,3f) and gasoline (boiling point 60-80°C) and acidified with 5M hydrochloric acid to produce The resulting product was collected by filtration and dried to give ethyl 3-oxo-4-(4-1-ly). Fluoromethylphenyl)-2,3-dihydro[1]henzovirano (4,3- c) Pyrazole-2-butyrate, melting point 112-115°C was obtained.

b) Ethyl 3-year-old xo-4-(4-trifluoromethylphenyl)-2,3- dihydro[l]benzopyrano[4,3] pyrazole-2-butyrate (3 ,0g) and 5M hydrochloric acid (30+nl) was stirred and heated at 96-105°C. Heated for 5 hours. The reaction mixture was allowed to cool and kept at ambient temperature for 24 hours. Obtained The resulting solids were collected by filtration, washed with water, then ether, and dried. So-4-(4-)lifluoromethylphenyl)-2,3-dihydroCI]ben Zopyrano(4,3-c)pyrazole-2-butyric acid, no shrinkage from melting point 189°C and 197-200°C.

C) 3-oxo-4-(4-trifluoromethyl) in dichloromethane (37ml) (ruphenyl)-2,3-dihydro(1)benzopyrano(4,3-c)pyrazo A stirred suspension of 2-butyric acid (1,8 g) was added to N,N,-dimethylformamide. (0,2[+11), followed by thionyl chloride (1,2 ml). blend was stirred at ambient temperature for 24 hours and then evaporated under reduced pressure to give 3-oxo-4-(4- trifluoromethylphenyl)-2,3-dihydro(1)benzopyrano(4,3 -c]] pyrazole-2-butyryl chloride was obtained.

d) Solution of acid chloride from step (C) in dry tetrahydrofuran (88ml) The mixture was stirred at 0.5°C and treated with concentrated aqueous ammonia solution (0.6ml). reaction mixture The mixture was stirred at 0-5°C for 1 hour. Add concentrated ammonia solution (0.2ml) was added and the mixture was stirred at 0-5°C for 0.75 hours.

The solid produced was collected by filtration, washed with tetrahydrofuran and water, and dried. Dry to give 3-oxo-4-(4-trifluoromethylphenyl)-2,3-dihyde. B[1]-Benzopyrano(4,3-c)pyrazole-2-butyramide, melting point 21 8-221"C was obtained.

Example 64 4-(4-chlorophenyl')-2-(2-hydroxy) synthesized in Example 47 ethyl)[l]benzopyrano[4,3 once]pyrazol-3(2dan)-one ( 28g) and thionyl chloride (300ml) were stirred and heated under reflux for 3.5 hours. Boiled. Excess thionyl chloride was distilled off under reduced pressure, and the residue was co-distilled with acetonitrile. The mixture was stirred. The mixture was filtered and the solid collected was recrystallized from dichloromethane. 2-(2-chloroethyl)-4-(4-chlorophenyl)[l]benzopyrano (4,3-c)] In the preparation of pyrazole-3 capsules, the active compound parts and 240 parts by weight of lactose were deagglomerated and mixed. hard gelatin mixture Each capsule contained 10 mg of active compound.

In preparing the capsules, 50 parts by weight of active compound, 300 parts by weight of lactose and and 3 parts by weight of magnesium stearate were deagglomerated and mixed. hard gelatin mixture Filled into tin capsules, each capsule contained 50 mg of active ingredient.

Example 67 Tablets were prepared from the following ingredients.

Weight part Active compound 10 Polyvinylpyrrolidone IO Magnesium phosphate 3 The active compound, lactose and some starch are deagglomerated and mixed, resulting in The mixture was granulated with a solution of polyvinylpyrrolidone in ethanol. dry granules was mixed with the remainder of the magnesium stearate and starch. Mixture then Compressed in a tablet machine to give active compounds a) 10 mg, b) 100 mg and c) 5 Tablets containing 00 mg were obtained.

Example 68 Tablets were prepared by the method of Example 67. Tablets in ethanol/dichloromethane ( 20% acetylphthalcellulose and 3% diethyl phthalate in 1: ]) The traditional method is to use a solution of enteric coating.

Example 69 In the preparation of crude drugs, half the amount of active compound 100% synthetic glycerol used as the crude drug base. The mixture was mixed with 1300 parts by weight of Lido, each containing 100 mg of the active ingredient. It was formed into a crude drug.

Example 70 In the preparation of cartilage, the active compound is added to the drug by complete homogenization until evenly distributed. Mixed into the base. The ointment was packed in a 10g amber bottle with a screw cap. .

Active compound 0.1g 10g white soft paraffin The compounds of the invention are immunomodulators, especially immunosuppressants, and can be administered at 200 mg/kg or may exhibit therapeutic activity at lower doses. Preferred compounds of the invention are Shows activity at 50 mg/kg or less. Treatment of preferred compounds of the invention Skin sensitization by parenterally administering compounds to BAL B/c mice to determine their therapeutic activity. This was proven by the sexual hypersensitivity test (CH test).

This test was conducted in the following manner.

Female BAL B/c mice with a weight range of 16 to 24 g were used in groups of 8. did. The abdomen of each mouse was shaved, sensitized, acetone:ethanol (volume ratio 1) : 5% W/V in 1) 4-ethoxymethylene-2-phenyl-2-year-old Kisashi 20μl of phosphorus-5-one (oxacilone) solution was applied to the shaved area. . Immediately after sensitization, test compounds were administered in sterile water (100 μm ) with a suspension of 1.5% V/V sorbitan ester under the trademark Tween 80. It was injected intraperitoneally as a suspension. 100 μm of the same suspension in the same manner every 24 hours. was injected for an additional 7 days. The dose used was selected from the following values: 50.30 , l013.1, 0.3.0.1.0.03 or 0.01 mg/kg.

Two groups of at least eight BALB/c mice were given no test compound during daily injections. simultaneously with each test in a manner similar to that described above except that Used as a control.

Seven days after sensitization, 1% W/V Oki in acetone:olive oil (3:l volume ratio) Add 10 μl of Sacilon solution to one ear of each test and control mouse. It was applied to the tested ear). (1.5% W/V oxa in acetone olive oil) A more effective test dose of Chiron was used in a small number of cases. ) 24 hours later, same The thickness of the animal's tested and untested ears was determined by the technician's screwdriver. Measured with a digital micrometer. Between the tested and untested ears of each animal The difference in thickness is a measure of the animal's responsiveness to oxacilone. test compound Comparison of reactivity between mice treated with the immunomodulator and control It shows the effectiveness of the test compound as a test compound. If three CH tests between treatment and control groups At least two (or, if three or more tests, the majority of tests) ) at its dosage (e.g., Int, Arch, Allergy, 3, 8, 2 46-259 (1970)), a reduction in ear swelling of up to 20% or more, the compound is considered active at a particular dose, and Du Statistically positive (p<0.05) by nnett test.

Each compound of formula I shown in Table A below is tested three times unless otherwise indicated. It was effective at 50 mg/kg in at least two of the tests. (Notes on the following table reference).

The lowest effective dose of each compound is shown in the table. Example (E8) Write the number or next to each compound. The numbers listed indicate the steps illustrating the synthesis of the compounds in the examples.

The following compounds were synthesized in a similar manner and further tested at 50 mg/kg in the CH test described above. I found out that kg is effective.

Lab-ru-2-yl]ethylpropionate, melting point 38-241°C (decomposition) (a) Activity at somg/kg in two tests each.

Compounds of the invention also show activity in a variety of other in vivo screens, including immunomodulatory The compounds exhibit utility as agents, particularly in suppressing immune responses. After administration of the compound It was administered orally or parenterally. Some compounds were generated anti-oxazolone anti- The xazolone-induced skin sensitization hypersensitivity test (CH test) described above due to changes in body mass. Measure the effect on humoral immunity by assaying serum collected at the end of the trial) and Sm1th SR, Terminell C.

Kipilman CT and Sm1th Y, J, [mmvnophal Also used by Macology 1981, 3 (2), 133-170 The compound is considered to be active in a graft-versus-host test similar to that of a human.

For example, the compound synthesized in the following example was also administered parenterally at 50 mg/kg. It was found to be active in the antibody test described above. Compound, if 50 determined by enzyme-linked immunosorbent assay (ELrSA) at a dose of mg/kg. If it results in a decrease in the relative serum anti-oxazolone antibody concentration, then It is considered active by a calculated factor of 0, 5 or more.

:0,D,(C,)-0,D,(T,)○,D,(C,)-　-〇,D,(C2 ) where O, D, (C,) are the optical densities of the control serum at a dilution of l/128 0, D, (C,) is the optical density of the control serum at a dilution of l/256 0, D, (TI) is the optical density of control serum diluted 1/128 Control and test serum containing 0.05% V/V Tween 20 (trade name) The solution was diluted with phosphate buffered saline (pH 7.3).

Active compounds of the above tests: Examples: 8b, 8c, 10-15, I8.20, 26.27.30.33.35 ．． 37.38.40, 42.44~47.49.52.55~64° Summary book For use as an immunomodulator, the following formula I (wherein R1 is hydrogen, Cia/, Cz- s alkanoyl C2-a alkoxycarbonyl, CONH2; R1 is C1-6 alkyl or C2-, alkenyl, both of which are cyapano, Trifluoromethyloxy, benzoyl, C2-, alkanoyloxy, C,1 cycloalkoxycarbonyl a 5- to 7-membered non-aromatic heterocyclic group containing atoms, CONR, phenoxy or C It may be substituted by I-@alkoxy, among which C1-, alkoxy Oxy (yo, halo, hydroxy, C1-, alkoxy (yo, C2-).

may be substituted with alkanoyloxy); R2 is hydrogen or chloro represents: R, represents chloro or trifluoromethyl; or R2 and R3 are combined; Forms a fused benzene ring: R4 is hydrogen, C1-, alkyl, C1-, alkoxy Or represents a halo: R, and R, may be the same or different and represent hydrogen, C11 alkyl or (representing njiru)

Claims (12)

[Claims] 1. The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼I (In the formula, R1 is hydrogen, cyano, C1-6 alkanoyl, C2-6 alkoxycar Bonyl, CONH2, or R1 is C1-6 alkyl or C2-6 alkyl. rukenyl, both of which are cyano, halo, trifluoromethyl, hydroxy , benzoyl, C2-6 alkanoyloxy, C3-8 cycloalkoxycarbo Nyl, a 5- to 7-membered non-aromatic heterocyclic group containing two oxygen heteroatoms, CONR 9R9, may be substituted with phenoxy or C1-6 alkoxy; Among these, C1-6 alkoxy is furthermore halo, hydroxy, C1-6 alkoxy or or C2-6 alkanoyloxy; R2 is hydrogen or represents chloro; R3 represents chloro or trifluoromethyl; or R2 and R3 are combined Forms a fused benzene ring; R4 is hydrogen, C1-6 alkyl, C1-6 alkoxy or representing a halo; R9 and R9 may be the same or different and are hydrogen, C1-6 alkyl or (representing benzyl) compound. 2. R2 represents hydrogen; R3 represents chloro or trifluoromethyl; R 1 represents (CH2)pJ, J is hydrogen, C1-6 alkoxy, carbamoyl, represents cyano or halo; R4 represents hydrogen or C1-6 alkoxy; 2. A compound according to claim 1, wherein p is 0, 1 or 2. 3. R1 is hydrogen, methyl, cyanomethyl, (CH2) halo, carbamoylmethyl or C1-4 alkoxyethyl. 4. Claim 3, wherein R6 represents methyl or 2-ethoxyethyl Compound. 5. The following compounds: 2-(2-ethoxyethyl)-9-methoxy-4-(4-trifluoromethylphenyl) phenyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one, 2 -Methyl-4-(4-trifluoromethylphenyl[1]benzopyrano[4,3 -c]pyrazol-3(2H)-one, 2-(2-ethoxyethyl)-4-(4-trifluoromethylphenyl) [1] Benzopyrano[4,3-c]pyrazol-3(2H)-one Compounds selected from. 6. A compound of formula I according to any one of claims 1 to 5 may be used as a medicament. 1. A pharmaceutical composition comprising a pharmaceutical carrier. 7. A pharmaceutical composition according to claim 6 in the form of a unit dose. 8. Therapeutic use of compounds of formula I according to any one of claims 1 to 5 A method of treating a disease by immunological assembly characterized by the administration of an effective amount. 9. Any one of claims 1 to 5 for use as an immunomodulator A compound of formula I as described in . 10. Claims in the manufacture of drugs for use in the treatment of diseases caused by immunological aggregation A compound of formula I according to any one of the ranges 1 to 5. 11. Next step: a) Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼Compounds II or their tautomers, Formula III▲There are mathematical formulas, chemical formulas, tables, etc.▼III (In the formula, R14 is (OQ)2 or (SQ)2 and R15 represents OQ or SQ or NQ2'; R14 represents =NH; and R15 represents OQ or SQ; or R1 4 represents =O, R15 represents hydrogen, halo or 1-imidazolyl; and Q and Q' represent a C1-4 alkyl group or a benzyl group) Reaction; b) Formula IV ▲There are mathematical formulas, chemical formulas, tables, etc.▼Compound of IV (in the formula, R16 represents hydrogen) or tautomers thereof [or in which R16 is a group COR18 (where R 18 represents hydrogen, C1-4 alkyl group, benzyl group or group R5) , R17 represents COR5] with a base; A method for synthesizing the compound according to claim 1, comprising: 12. The following formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II (In the formula, R1 and R4 are (as defined in Section 1).